As scientists with a keen interest in non-Hodgkin lymphoma (NHL), we recognize the unique potential for the Women's Health Initiative (WHI) to advance the state of knowledge of NHL etiology. The prospective design of the sample collection and the different types of biologic samples within this well-described cohort make these samples unusually informative. There is intriguing evidence that markers of B-cell stimulation may be implicated in development of B-cell NHL, from studies among immunocompromised patient populations. We propose a nested case-control study of biologic markers of a B-cell stimulatory host environment as predictors of B-cell NHL among 500 cases and 500 pair-matched controls from the WHI Observational Study (OS), among whom biologic amples were collected an average of 10 years before NHL diagnosis. Our primary aims are to: 1) Evaluate the risk of B-cell NHL associated with immune parameters, measured in prediagnostic plasma/serum, that are indicative of a B-cell stimulatory host environment, including levels of certain cytokines (e.g., IL6, IL 10, TNFa), cytokine-like molecules (sCD23), soluble cytokine receptors sCD27, sCD30), and other molecules involved in B-cell response (sCD44, CXCL 13);2) Measure EBV DNA load and antibodies to key. EBV antigens (VCA, EBNA 1, and EA-D), for estimation of the risk of B-cell NHL associated with EBV, a cause of B-cell proliferation;and 3) Investigate whether observed associations differ by major NHL subtype, including diffuse large B-celllymphoma (DLBCL) and follcular lymphoma. As a secondary aim, we wil describe the patterns of association according to the number of years between blood sample collection and NHL diagnosis, in order to inform our interpretation of marker-NHL associations as potentially etiologic or as a reflection of early NHL pathogenesis. Ours will be the first study to investigate these hypotheses in an apparently immunocompetent population. After carefully characterizing this pathway, these data will become a useful resource for future studies of NHL in the WHI.